Influenza viruses commonly infect the upper respitory tract of mammals, including humans, pigs, horses, mink, seals, and whales. Influenza viruses can also have gastrointestinal tropism in bird species. Seasonal epidemics of flu generally occur after January and typically affect 10-20% of the general human population. Influenza viruses are members of the Orthomyxoviridae family of RNA viruses. Such viruses are commonly referred to as enveloped viruses. The three types of influenza viruses are A, B, and C. Most animal species can be infected with Influenza A. Influenza B and C were once thought to only infect humans, but researchers have recently discovered seals can be infected with Influenza B.
It is well known that influenza viruses can mutate and form new strains from season to season. New strains in human populations typically develop from other animal species (e.g., birds). Viral transmission from birds to animals is thought to proceed through an intermediate animal (e.g., swine), since human and avian influenza viruses are quite different. Occasionally, however, avian to human transmission can occur.
Any subject can be susceptible to influenza viral infection (even healthy subjects), and serious problems from influenza can happen at any age. While most subjects who get influenza will recover in a few days to less than 2 weeks, some subjects can develop complications (e.g., pneumonia, bronchitis, and sinus and ear infections) or experience exacerbation of chronic health problems such as asthma or chongestive heart failure. Such complications and exacerbation of chronic health problems can lead to the death of an infected subject. The infamous influenza pandemic of 1918-1919, for example, killed an estimated 20-40 million people worldwide. Further, in non-pandemic years, an average of about 36,000 people per year in the United States die from influenza, and more than 200,000 have to be admitted to the hospital as a result of influenza. As influenza is caused by a virus, antibiotics (e.g., penicillin) do not treat the infection. The current method of preventing the flu is to get an influenza vaccine annually, prior to flu season.
The influenza A virus particle or virion is 80-120 nm in diameter. Unusual for a virus, the influenza A genome is not a single piece of nucleic acid; instead, it contains eight pieces of segmented negative-sense RNA (13.5 kilobases total), which encode 10 proteins (HA (hemagglutinin), NA (neuraminidase), NP (nucleoprotein), M1, M2, NS1, PA, PB1, PB1-F2, PB2). Hemagglutinin and neuraminidase are two large glycoproteins found on the outside of the viral particles. Neuraminidase is an enzyme involved in the release of progeny virus from infected cells by cleaving sugars that bind the mature viral particles. By contrast, hemagglutinin is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the target cell. Because a virus must bind to the target cell, inhibition of viral binding prevents infection.
The ability of a virus (e.g., influenza) to overtake the replication infrastructure of a host cell and effect virus replication begins with recognition by the virus of certain receptors on the host cell's membrane. This process can be mediated by a surface protein or multiple surface proteins on the virion, e.g., hemagglutinin (HA) of influenza virus. Once HA is synthesized on membrane bound ribosomes, its polypeptide chain is eventually cleaved into two chains of 328 and 221 amino acids known as HA1 and HA2, which can be held together by disulfide bonds. Three HA monomers (each with one HA1 and HA2) can trimerize and be transported to the plasma membrane, where the HA2 tails anchor the monomers to the membrane, with the large part of the monomers protruding outside of the membrane. It is believed that about 20 residues at the N-terminal end of HA2 are associated with the mechanism by which virus particles penetrate a host cell. This N-terminal portion is known as the fusion peptide.
Influenza viruses bind through hemagglutinin onto sialic acid sugars on the surfaces of epithelial cells. The predominant type of sialic acids is N-acetylneuraminic acid (Neu5Ac). Two types of sialic acids, Neu5Ac α(2,3)-Gal and Neu5Ac α(2,6)-Gal, both of which can be recognized as a receptor by influenza viruses, are important for viral infection of cells. Once a virus recognizes the sialic acids, cell fusion is then necessary to complete the transfer of the influenza genome into the target cell.
The cell imports the virus by endocytosis. In the acidic endosome, part of the hemagglutinin protein fuses the viral envelope with the vacuole's membrane, thus releasing the viral RNA (vRNA) molecules, accessory proteins and RNA-dependent RNA transcriptase into the cytoplasm.
HA functions in at least two known roles during viral infection. First, HA binds to the cell, and second, HA acts as a membrane fusogen. HA protein binds to sialic acid residues of glycosylated receptor molecules on target cell surfaces. Once bound, the virus can then enter the cell through endocytosis. The sialic acid binding site has been shown by X-ray crystallography to be located at the tip of an HA subunit within the jelly roll motif.